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1.
ACS Chem Neurosci ; 15(7): 1432-1455, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38477556

RESUMO

Alzheimer's disease (AD) is the most prevalent cause of dementia characterized by a progressive cognitive decline. Addressing neuroinflammation represents a promising therapeutic avenue to treat AD; however, the development of effective antineuroinflammatory compounds is often hindered by their limited blood-brain barrier (BBB) permeability. Consequently, there is an urgent need for accurate, preclinical AD patient-specific BBB models to facilitate the early identification of immunomodulatory drugs capable of efficiently crossing the human AD BBB. This study presents a unique approach to BBB drug permeability screening as it utilizes the familial AD patient-derived induced brain endothelial-like cell (iBEC)-based model, which exhibits increased disease relevance and serves as an improved BBB drug permeability assessment tool when compared to traditionally employed in vitro models. To demonstrate its utility as a small molecule drug candidate screening platform, we investigated the effects of diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (CuII(atsm)) and a library of metal bis(thiosemicarbazone) complexes─a class of compounds exhibiting antineuroinflammatory therapeutic potential in neurodegenerative disorders. By evaluating the toxicity, cellular accumulation, and permeability of those compounds in the AD patient-derived iBEC, we have identified 3,4-hexanedione bis(N(4)-methylthiosemicarbazonato)copper(II) (CuII(dtsm)) as a candidate with good transport across the AD BBB. Furthermore, we have developed a multiplex approach where AD patient-derived iBEC were combined with immune modulators TNFα and IFNγ to establish an in vitro model representing the characteristic neuroinflammatory phenotype at the patient's BBB. Here, we observed that treatment with CuII(dtsm) not only reduced the expression of proinflammatory cytokine genes but also reversed the detrimental effects of TNFα and IFNγ on the integrity and function of the AD iBEC monolayer. This suggests a novel pathway through which copper bis(thiosemicarbazone) complexes may exert neurotherapeutic effects on AD by mitigating BBB neuroinflammation and related BBB integrity impairment. Together, the presented model provides an effective and easily scalable in vitro BBB platform for screening AD drug candidates. Its improved translational potential makes it a valuable tool for advancing the development of metal-based compounds aimed at modulating neuroinflammation in AD.


Assuntos
Doença de Alzheimer , Tiossemicarbazonas , Humanos , Barreira Hematoencefálica/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Cobre/metabolismo , Doenças Neuroinflamatórias , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/metabolismo , Tiossemicarbazonas/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo
2.
Bioorg Chem ; 143: 107022, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38142558

RESUMO

Liver fibrosis remains a global health challenge due to its rapidly rising prevalence and limited treatment options. The orphan nuclear receptor Nur77 has been implicated in regulation of autophagy and liver fibrosis. Targeting Nur77-mediated autophagic flux may thus be a new promising strategy against hepatic fibrosis. In this study, we synthesized four types of Nur77-based thiourea derivatives to determine their anti-hepatic fibrosis activity. Among the synthesized thiourea derivatives, 9e was the most potent inhibitor of hepatic stellate cells (HSCs) proliferation and activation. This compound could directly bind to Nur77 and inhibit TGF-ß1-induced α-SMA and COLA1 expression in a Nur77-dependent manner. In vivo, 9e significantly reduced CCl4-mediated hepatic inflammation response and extracellular matrix (ECM) production, revealing that 9e is capable of blocking the progression of hepatic fibrosis. Mechanistically, 9e induced Nur77 expression and enhanced autophagic flux by inhibiting the mTORC1 signaling pathway in vitro and in vivo. Thus, the Nur77-targeted lead 9e may serve as a promising candidate for treatment of chronic liver fibrosis.


Assuntos
Antifibróticos , Tiossemicarbazonas , Humanos , Tiossemicarbazonas/metabolismo , Células Estreladas do Fígado , Fígado/metabolismo , Cirrose Hepática/metabolismo , Tioureia/metabolismo , Tetracloreto de Carbono
3.
Int J Mol Sci ; 23(18)2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36142627

RESUMO

Neuroinflammation has a major role in several brain disorders including Alzheimer's disease (AD), yet at present there are no effective anti-neuroinflammatory therapeutics available. Copper(II) complexes of bis(thiosemicarbazones) (CuII(gtsm) and CuII(atsm)) have broad therapeutic actions in preclinical models of neurodegeneration, with CuII(atsm) demonstrating beneficial outcomes on neuroinflammatory markers in vitro and in vivo. These findings suggest that copper(II) complexes could be harnessed as a new approach to modulate immune function in neurodegenerative diseases. In this study, we examined the anti-neuroinflammatory action of several low-molecular-weight, charge-neutral and lipophilic copper(II) complexes. Our analysis revealed that one compound, a thiosemicarbazone-pyridylhydrazone copper(II) complex (CuL5), delivered copper into cells in vitro and increased the concentration of copper in the brain in vivo. In a primary murine microglia culture, CuL5 was shown to decrease secretion of pro-inflammatory cytokine macrophage chemoattractant protein 1 (MCP-1) and expression of tumor necrosis factor alpha (Tnf), increase expression of metallothionein (Mt1), and modulate expression of Alzheimer's disease-associated risk genes, Trem2 and Cd33. CuL5 also improved the phagocytic function of microglia in vitro. In 5xFAD model AD mice, treatment with CuL5 led to an improved performance in a spatial working memory test, while, interestingly, increased accumulation of amyloid plaques in treated mice. These findings demonstrate that CuL5 can induce anti-neuroinflammatory effects in vitro and provide selective benefit in vivo. The outcomes provide further support for the development of copper-based compounds to modulate neuroinflammation in brain diseases.


Assuntos
Doença de Alzheimer , Tiossemicarbazonas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Fatores Quimiotáticos/metabolismo , Complexos de Coordenação , Cobre/metabolismo , Modelos Animais de Doenças , Glicoproteínas de Membrana/metabolismo , Metalotioneína/metabolismo , Camundongos , Microglia/metabolismo , Receptores Imunológicos/metabolismo , Tiossemicarbazonas/metabolismo , Tiossemicarbazonas/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
4.
J Biomol Struct Dyn ; 40(18): 8365-8374, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-33890552

RESUMO

Mycobacterium tuberculosis (Mtb) is an infectious disease that affects nearly 9.6 million people every year. Metals are important determinants of growth and pathogenicity of mycobacterium. In the present study, we have analyzed protein-protein interaction networks belonging to the iron, sulfur and molybdenum metabolism of Mycobacterium. Our analysis has identified some of the important target proteins one among them being irtA. Iron taken up by siderophores from the host is transported to irtA through which iron enters Mycobacterium. Thus, irtA plays a major role as an iron transporter in Mycobacterium. As irtA protein structure was not solved experimentally, we have predicted 3D structure of irtA. After successful model evaluation, we have identified thiosemicarbazones as possible drug candidates for irtA. Henceforth, we have designed five analogues of thiosemicarbazones and tested in silico for their efficacy against irtA using molecular docking, among them analogue 1 showed a very good efficacy.Communicated by Ramaswamy H. Sarma.


Assuntos
Mycobacterium tuberculosis , Tiossemicarbazonas , Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Bactérias/química , Humanos , Ferro/metabolismo , Simulação de Acoplamento Molecular , Molibdênio/metabolismo , Mycobacterium tuberculosis/metabolismo , Sideróforos/química , Sideróforos/metabolismo , Enxofre/metabolismo , Tiossemicarbazonas/metabolismo
5.
J Inorg Biochem ; 223: 111543, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34298306

RESUMO

Considering the promising previous results on the remarkable activity exhibited by cobalt(III) and manganese(II) thiosemicarbazone compounds as antibacterial agents, the present study aimed to prepare and then evaluate the antibacterial activity of two different types of Cu(II) complexes based on a 2-acetylpyridine-N(4)-methyl-thiosemicarbazone ligand (Hatc-Me), a monomer complex [CuCl(atc-Me)] and a novel dinuclear complex [{Cu(µ-atc-Me)}2µ-SO4]. The compounds were characterized by infrared spectra, ultraviolet visible and CHN elemental analysis. In addition, the crystalline structures of the complexes were determined by single-crystal X-ray diffraction. In both cases, the Schiff base ligand coordinated in a tridentate mode via the pyridine nitrogen, imine nitrogen and sulfur atoms. The two Cu(II) atoms in the dimer are five coordinate, consisting of three NNS-donor atoms from the thiosemicarbazone ligand connected by a sulfate bridge. The Hirshfeld surface and energy framework of the complexes were additionally analyzed to verify the intermolecular interactions. The biological activity of the Cu(II) salts, the free ligand and its Cu(II) complexes was evaluated against six strains of mycobacteria including Mycobacterium tuberculosis. The complexes showed promising results as antibacterial agents for M. avium and M. tuberculosis, which ranged from 6.12 to 12.73 µM. Furthermore, molecular docking analysis was performed and the binding energy of the docked compound [{Cu(µ-atc-Me)}2µ-SO4] with M. tuberculosis and M. avium strains were extremely favorable (-11.11 and - 14.03 kcal/mol, respectively). The in silico results show that the complexes are potential candidates for the development of new antimycobacterial drugs.


Assuntos
Antituberculosos/farmacologia , Complexos de Coordenação/farmacologia , Tiossemicarbazonas/farmacologia , Antituberculosos/síntese química , Antituberculosos/metabolismo , Antituberculosos/farmacocinética , Proteínas de Bactérias/metabolismo , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacocinética , Cobre/química , Ligantes , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium avium/efeitos dos fármacos , Mycobacterium kansasii/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Ligação Proteica , Relação Estrutura-Atividade , Termodinâmica , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/metabolismo , Tiossemicarbazonas/farmacocinética
6.
Future Med Chem ; 13(14): 1185-1201, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34148377

RESUMO

Aim: Indole is an important component of many drug molecules, and its conjugation with thiosemicarbazone moiety would be advantageous in finding lead compounds for the development of diabetic complications. Methodology: We have designed, synthesized and evaluated a series of 17 indole-thiosemicarbazones (3a-q) as aldose reductase (ALR2) and aldehyde reductase (ALR1) inhibitors. Results: After in vitro evaluation, all indole-thiosemicarbazones showed significant inhibition against both enzyme ALR1 and ALR2 with IC50 in range of 0.42-20.7 and 1.02-19.1 µM, respectively. The docking study was also carried out to consider the putative binding of molecules with the target enzymes. Conclusion: Compound 3f was found to be most active and selective for ALR2. The indole-thiosemicarbazones series described here has selective hits for diabetes-mellitus-associated complications.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Indóis/química , Tiossemicarbazonas/química , Aldeído Redutase/metabolismo , Sítios de Ligação , Domínio Catalítico , Inibidores Enzimáticos/metabolismo , Humanos , Imidazolidinas/química , Imidazolidinas/metabolismo , Simulação de Acoplamento Molecular , NADP/química , NADP/metabolismo , Relação Estrutura-Atividade , Tiossemicarbazonas/metabolismo
7.
Molecules ; 26(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063080

RESUMO

Copper(II) complexes of thiosemicarbazones (TSCs) often exhibit anticancer properties, and their pharmacokinetic behavior can be affected by their interaction with blood transport proteins. Interaction of copper(II) complexes of an {N,N,S} donor α-N-pyridyl TSC (Triapine) and an {O,N,S} donor 2-hydroxybenzaldehyde TSC (STSC) with human serum albumin (HSA) was investigated by UV-visible and electron paramagnetic resonance spectroscopy at physiological pH. Asp-Ala-His-Lys and the monodentate N-methylimidazole were also applied as binding models. Conditional formation constants were determined for the ternary copper(II)-TSC complexes formed with HSA, DAHK, and N-methylimidazole based on the spectral changes of both charge transfer and d-d bands. The neutral N-methylimidazole displays a similar binding affinity to both TSC complexes. The partially negatively charged tetrapeptide binds stronger to the positively charged Triapine complex in comparison to the neutral STSC complex, while the opposite trend was observed for HSA, which demonstrates the limitations of the use of simple ligands to model the protein binding. The studied TSC complexes are able to bind to HSA in a fast process, and the conditional constants suggest that their binding strength is only weak-to-moderate.


Assuntos
Cobre/metabolismo , Albumina Sérica Humana/metabolismo , Tiossemicarbazonas/metabolismo , Anisotropia , Simulação por Computador , Humanos , Oligopeptídeos/química , Oxirredução , Ligação Proteica , Piridinas/química , Soluções , Espectrofotometria Ultravioleta , Tiossemicarbazonas/química , Fatores de Tempo
8.
Int J Mol Sci ; 22(10)2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069455

RESUMO

In this work, we report solvent-induced complexation properties of a new N2S2 tetradentate bis-thiosemicarbazone ligand (H2LI), prepared by the condensation of 4-phenylthiosemicarbazide with bis-aldehyde, namely 2,2'-(ethane-1,2-diylbis(oxy)dibenzaldehyde, towards nickel(II). Using ethanol as a reaction medium allowed the isolation of a discrete mononuclear homoleptic complex [NiLI] (1), for which its crystal structure contains three independent molecules, namely 1-I, 1-II, and 1-III, in the asymmetric unit. The doubly deprotonated ligand LI in the structure of 1 is coordinated in a cis-manner through the azomethine nitrogen atoms and the thiocarbonyl sulfur atoms. The coordination geometry around metal centers in all the three crystallographically independent molecules of 1 is best described as the seesaw structure. Interestingly, using methanol as a reaction medium in the same synthesis allowed for the isolation of a discrete mononuclear homoleptic complex [Ni(LII)2] (2), where LII is a monodeprotonated ligand 2-(2-(2-(2-(dimethoxymethyl)phenoxy)ethoxy)benzylidene)-N-phenylhydrazine-1-carbothioamide (HLII). The ligand LII was formed in situ from the reaction of LI with methanol upon coordination to the metal center under synthetic conditions. In the structure of 2, two ligands LII are coordinated in a trans-manner through the azomethine nitrogen atom and the thiocarbonyl sulfur atom, also yielding a seesaw coordination geometry around the metal center. The charge and energy decomposition scheme ETS-NOCV allows for the conclusion that both structures are stabilized by a bunch of London dispersion-driven intermolecular interactions, including predominantly N-H∙∙∙S and N-H∙∙∙O hydrogen bonds in 1 and 2, respectively; they are further augmented by less typical C-H∙∙∙X (where X = S, N, O, π), CH∙∙∙HC, π∙∙∙π stacking and the most striking, attractive long-range intermolecular C-H∙∙∙Ni preagostic interactions. The latter are found to be determined by both stabilizing Coulomb forces and an exchange-correlation contribution as revealed by the IQA energy decomposition scheme. Interestingly, the analogous long-range C-H∙∙∙S interactions are characterized by a repulsive Coulomb contribution and the prevailing attractive exchange-correlation constituent. The electron density of the delocalized bonds (EDDB) method shows that the nickel(II) atom shares only ~0.8|e| due to the σ-conjugation with the adjacent in-plane atoms, demonstrating a very weak σ-metalloaromatic character.


Assuntos
Níquel/química , Tiossemicarbazonas/química , Aldeídos/química , Compostos Azo/química , Complexos de Coordenação/química , Cristalografia por Raios X/métodos , Ligação de Hidrogênio , Ligantes , Modelos Moleculares , Estrutura Molecular , Solventes/química , Tiossemicarbazonas/metabolismo
9.
ChemistryOpen ; 10(4): 486-492, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33908707

RESUMO

The Cu(II)-diacetyl-bis (N4-methylthiosemicarbazone) complex (ATSM-Cu(II)) has been suggested as a promising positron emission tomography (PET) agent for hypoxia imaging. Several in-vivo studies have shown its potential to detect hypoxic tumors. However, its uptake mechanism and its specificity to various cancer cell lines have been less studied. Herein, we tested ATSM-Cu(II) toxicity, uptake, and reduction, using four different cell types: (1) mouse breast cancer cells (DA-3), (2) human embryonic kidney cells (HEK-293), (3) breast cancer cells (MCF-7), and (4) cervical cancer cells (Hela) under normoxic and hypoxic conditions. We showed that ATSM-Cu(II) is toxic to breast cancer cells under normoxic and hypoxic conditions; however, it is not toxic to normal HEK-293 non-cancer cells. We showed that the Cu(I) content in breast cancer cell after treatment with ATSM-Cu(II) under hypoxic conditions is higher than in normal cells, despite that the uptake of ATSM-Cu(II) is a bit higher in normal cells than in breast cancer cells. This study suggests that the redox potential of ATSM-Cu(II) is higher in breast cancer cells than in normal cells; thus, its toxicity to cancer cells is increased.


Assuntos
Hipóxia/metabolismo , Compostos Organometálicos/metabolismo , Tiossemicarbazonas/metabolismo , Animais , Linhagem Celular Tumoral , Complexos de Coordenação , Radioisótopos de Cobre/química , Radioisótopos de Cobre/metabolismo , Transportador de Cobre 1/metabolismo , Células HEK293 , Humanos , Camundongos , Compostos Organometálicos/química , Compostos Organometálicos/toxicidade , Oxirredução , Tiossemicarbazonas/química , Tiossemicarbazonas/toxicidade
10.
Bioorg Chem ; 107: 104554, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33383322

RESUMO

With the fading of 'one drug-one target' approach, Multi-Target-Directed Ligands (MTDL) has become a central idea in modern Medicinal Chemistry. The present study aimed to design, develop and characterize a novel series of 4-(Diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) and evaluates their biological activity against cholinesterase, carbonic anhydrases and α-glycosidase enzymes. The hCA I isoform was inhibited by these novel 4-(diethylamino)-salicylaldehyde-based thiosemicarbazones (3a-p) in low nanomolar levels, the Ki of which differed between 407.73 ± 43.71 and 1104.11 ± 80.66 nM. Against the physiologically dominant isoform hCA II, the novel compounds demonstrated Kis varying from 323.04 ± 56.88 to 991.62 ± 77.26 nM. Also, these novel 4-(diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) effectively inhibited AChE, with Ki values in the range of 121.74 ± 23.52 to 548.63 ± 73.74 nM. For BChE, Ki values were obtained with in the range of 132.85 ± 12.53 to 618.53 ± 74.23 nM. For α-glycosidase, the most effective Ki values of 3b, 3k, and 3g were with Ki values of 77.85 ± 10.64, 96.15 ± 9.64, and 124.95 ± 11.44 nM, respectively. We have identified inhibition mechanism of 3b, 3g, 3k, and 3n on α-glycosidase AChE, hCA I, hCA II, and BChE enzyme activities. Hydrazine-1-carbothioamide and hydroxybenzylidene moieties of compounds play an important role in the inhibition of AChE, hCA I, and hCA II enzymes. Hydroxybenzylidene moieties are critical for inhibition of both BChE and α-glycosidase enzymes. The findings of in vitro and in silico evaluations indicate 4-(diethylamino)-salicylaldehyde-based thiosemicarbazone scaffold to be a promising hit for drug development for multifactorial diseases like Alzheimer's disease.


Assuntos
Acetilcolinesterase/química , Butirilcolinesterase/química , Anidrases Carbônicas/química , Glicosídeo Hidrolases/antagonistas & inibidores , Tiossemicarbazonas/química , Acetilcolinesterase/metabolismo , Aldeídos/química , Sítios de Ligação , Butirilcolinesterase/metabolismo , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/metabolismo , Anidrases Carbônicas/metabolismo , Domínio Catalítico , Glicosídeo Hidrolases/metabolismo , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Cinética , Ligantes , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tiossemicarbazonas/metabolismo
11.
Chembiochem ; 22(4): 694-704, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-32909347

RESUMO

Three chiral tridentate N^N^S coordinating pyridine-carbaldehyde (S)-N4-(α-methylbenzyl)thiosemicarbazones (HTSCmB) were synthesised along with lysine-modified derivatives. One of them was selected and covalently conjugated to the cell-penetrating peptide sC18 by solid-phase peptide synthesis. The HTSCmB model ligands, the HTSCLp derivatives and the peptide conjugate rapidly and quantitatively form very stable PtII chlorido complexes [Pt(TSC)Cl] when treated with K2 PtCl4 in solution. The Pt(CN) derivatives were obtained from one TSCmB model complex and the peptide conjugate complex through Cl- →CN- exchange. Ligands and complexes were characterised by NMR, IR spectroscopy, HR-ESI-MS and single-crystal XRD. Intriguingly, no decrease in cell viability was observed when testing the biological activity of the lysine-tagged HdpyTSCLp, its sC18 conjugate HdpyTSCL-sC18 or the PtCl and Pt(CN) conjugate complexes in three different cell lines. Thus, given the facile and effective preparation of such Pt-TSC-peptide conjugates, these systems might pave the way for future use in late-stage labelling with Pt radionuclides and application in nuclear medicine.


Assuntos
Peptídeos Penetradores de Células/química , Lisina/química , Compostos Organometálicos/química , Fragmentos de Peptídeos/química , Platina/química , Tiossemicarbazonas/química , Peptídeos Penetradores de Células/metabolismo , Humanos , Lisina/metabolismo , Compostos Organometálicos/metabolismo , Fragmentos de Peptídeos/metabolismo , Platina/metabolismo , Tiossemicarbazonas/metabolismo
12.
Inorg Chem ; 59(23): 17109-17122, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33231439

RESUMO

Metal complexes have numerous applications in the current era, particularly in the field of pharmaceutical chemistry and catalysis. A novel synthetic approach for the same is always a beneficial addition to the literature. Henceforth, for the first time, we report the formation of three new Pd(II) complexes through the Michael addition pathway. Three chromone-based thiosemicarbazone ligands (SVSL1-SVSL3) and Pd(II) complexes (1-3) were synthesized and characterized by analytical and spectroscopic tools. The Michael addition pathway for the formation of complexes was confirmed by spectroscopic studies. Distorted square planar structure of complex 2 was confirmed by single-crystal X-ray diffraction. Complexes 1-3 were subjected to DNA- and BSA-binding studies. The complex with cyclohexyl substituent on the terminal N of thiosemicarbazone (3) showed the highest binding efficacy toward these biomolecules, which was further understood through molecular docking studies. The anticancer potential of these complexes was studied preliminarily by using MTT assay in cancer and normal cell lines along with the benchmark drugs (cisplatin, carboplatin, and gemcitabine). It was found that complex 3 was highly toxic toward MDA-MB-231 and AsPC-1 cancer cells with IC50 values of 0.5 and 0.9 µM, respectively, and was more efficient than the standard drugs. The programmed cell death mechanism of the complexes in MDA-MB-231 cancer cells was confirmed. Furthermore, the complexes induced apoptosis via ROS-mediated mitochondrial signaling pathway. Conveniently, all the complexes showed less toxicity (≥50 µM) against MCF-10a normal cell line. Molecular docking studies were performed with VEGFR2, EGFR, and SARS-CoV-2 main protease to illustrate the binding efficiency of the complexes with these receptors. To our surprise, binding potential of the complexes with SARS-CoV-2 main protease was higher than that with chloroquine and hydroxychloroquine.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , SARS-CoV-2/enzimologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Cromonas/síntese química , Cromonas/metabolismo , Cromonas/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Proteases 3C de Coronavírus/metabolismo , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Humanos , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/metabolismo , Substâncias Intercalantes/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Paládio/química , Ligação Proteica , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/metabolismo , Tiossemicarbazonas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
13.
J Med Chem ; 63(22): 13719-13732, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33190481

RESUMO

COTI-2 is a novel anticancer thiosemicarbazone in phase I clinical trial. However, the effects of metal complexation (a main characteristic of thiosemicarbazones) and acquired resistance mechanisms are widely unknown. Therefore, in this study, the copper and iron complexes of COTI-2 were synthesized and evaluated for their anticancer activity and impact on drug resistance in comparison to metal-free thiosemicarbazones. Investigations using Triapine-resistant SW480/Tria and newly established COTI-2-resistant SW480/Coti cells revealed distinct structure-activity relationships. SW480/Coti cells were found to overexpress ABCC1, and COTI-2 being a substrate for this efflux pump. This was unexpected, as ABCC1 has strong selectivity for glutathione adducts. The recognition by ABCC1 could be explained by the reduction kinetics of a ternary Cu-COTI-2 complex with glutathione. Thus, only thiosemicarbazones forming stable, nonreducible copper(II)-glutathione adducts are recognized and, in turn, effluxed by ABCC1. This reveals a crucial connection between copper complex chemistry, glutathione interaction, and the resistance profile of clinically relevant thiosemicarbazones.


Assuntos
Aminoquinolinas/metabolismo , Cobre/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Glutationa/metabolismo , Líquido Intracelular/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Tiossemicarbazonas/metabolismo , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cobre/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glutationa/química , Humanos , Líquido Intracelular/efeitos dos fármacos , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Difração de Raios X
14.
Molecules ; 25(21)2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33126761

RESUMO

Dipeptidyl peptidase-4 (DPP-4) inhibition has been recognized as a promising approach to develop safe and potent antidiabetic agents for the management of type 2 diabetes. In this context, new thiosemicarbazones (2a-o) were prepared efficiently by the reaction of aromatic aldehydes with 4-[4-(1H-pyrazol-1-yl)phenyl]thiosemicarbazide (1), which was obtained via the reaction of 4-(1H-pyrazol-1-yl)phenyl isothiocyanate with hydrazine hydrate. Compounds 2a-o were evaluated for their DPP-4 inhibitory effects based on a convenient fluorescence-based assay. 4-[4-(1H-pyrazol-1-yl)phenyl]-1-(4-bromobenzylidene)thiosemicarbazide (2f) was identified as the most effective DPP-4 inhibitor in this series with an IC50 value of 1.266 ± 0.264 nM when compared with sitagliptin (IC50 = 4.380 ± 0.319 nM). MTT test was carried out to assess the cytotoxic effects of compounds 2a-o on NIH/3T3 mouse embryonic fibroblast (normal) cell line. According to cytotoxicity assay, compound 2f showed cytotoxicity towards NIH/3T3 cell line with an IC50 value higher than 500 µM pointing out its favourable safety profile. Molecular docking studies indicated that compound 2f presented π-π interactions with Arg358 and Tyr666 via pyrazole scaffold and 4-bromophenyl substituent, respectively. Overall, in vitro and in silico studies put emphasis on that compound 2f attracts a great notice as a drug-like DPP-4 inhibitor for further antidiabetic research.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Desenho de Fármacos , Pirazóis/química , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/farmacologia , Técnicas de Química Sintética , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/metabolismo , Simulação de Acoplamento Molecular , Conformação Proteica , Tiossemicarbazonas/química , Tiossemicarbazonas/metabolismo
15.
J Inorg Biochem ; 203: 110875, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31706223

RESUMO

One mononuclear and another dinuclear Pd(II) complexes bearing a α-N-heterocyclic thiosemicarbazone ligand have been synthesized, fully characterized and studied as biological agents. In both complexes, the palladium center is coordinated to 3,5-diacetyl-1,2,4-triazol bis(N4,N4-dimethylthiosemicarbazone) via three sites (N, N and S). Their binding ability to DNA has been evaluated using spectroscopic and biophysical techniques. Molecular docking and molecular dynamics calculations supports the existence of a minor groove binding mode between the studied compounds and DNA.


Assuntos
Complexos de Coordenação/química , DNA/metabolismo , Tiossemicarbazonas/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , DNA/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Paládio/química , Eletricidade Estática , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/metabolismo
16.
Sci Rep ; 9(1): 16006, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690816

RESUMO

Cardiovascular progenitor cells (CPCs) derived from human pluripotent stem cells (hPSCs) are proposed to be invaluable cell sources for experimental and clinical studies. This wide range of applications necessitates large-scale production of CPCs in an in vitro culture system, which enables both expansion and maintenance of these cells. In this study, we aimed to develop a defined and efficient culture medium that uses signaling factors for large-scale expansion of early CPCs, called cardiogenic mesodermal cells (CMCs), which were derived from hPSCs. Chemical screening resulted in a medium that contained a reproducible combination of three factors (A83-01, bFGF, and CHIR99021) that generated 1014 CMCs after 10 passages without the propensity for tumorigenicity. Expanded CMCs retained their gene expression pattern, chromosomal stability, and differentiation tendency through several passages and showed both the safety and possible cardio-protective potentials when transplanted into the infarcted rat myocardium. These CMCs were efficiently cryopreserved for an extended period of time. This culture medium could be used for both adherent and suspension culture conditions, for which the latter is required for large-scale CMC production. Taken together, hPSC-derived CMCs exhibited self-renewal capacity in our simple, reproducible, and defined medium. These cells might ultimately be potential, promising cell sources for cardiovascular studies.


Assuntos
Sistema Cardiovascular/citologia , Meios de Cultura/metabolismo , Células-Tronco Pluripotentes/citologia , Animais , Sistema Cardiovascular/metabolismo , Diferenciação Celular , Proliferação de Células , Meios de Cultura/química , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Masculino , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/transplante , Pirazóis/metabolismo , Piridinas/metabolismo , Pirimidinas/metabolismo , Ratos , Ratos Wistar , Tiossemicarbazonas/metabolismo
17.
J Photochem Photobiol B ; 199: 111585, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31450131

RESUMO

Thiosemicarbazone derivatives are known for their broad biological activity including their antitumor potency. The aim of the current study was to examine the effect of a novel series of non-toxic iron chelators on the accumulation of protoporphyrin IX after external 5-aminolevulonic acid administration. From this series we selected one the most promising derivative which causes a pronounced increase in the concentration of protoporphyrin IX. The increase of the photosensitizer concentration is necessary for the trigger the efficient therapeutic effect of the photodynamic reaction. For selected compound 2 we performed an examination of a panel of the genes that are involved in the heme biosynthesis and degradation. Results indicated the crucial roles of ferrochelatase and heme oxygenase in the described processes. Surprisingly, there was a strict dependence on the type of the tested cell line. A decrease in the expression of the two aforementioned enzymes after incubation with compound 2 and 5-aminolevulonic acid is a commonly known fact and we detected this trend for the MCF-7 and HCT 116 cell lines. However, we noticed the upregulation of the tested targets for the Hs683 cells. These unconventional results prompted us to do a more in-depth analysis of the described processes. In conclusion, we found that compound 2 is a novel, highly effective booster of photodynamic therapy that has prospective applications.


Assuntos
Antineoplásicos/síntese química , Ferro/química , Fármacos Fotossensibilizantes/síntese química , Protoporfirinas/química , Tiossemicarbazonas/metabolismo , Células A549 , Ácido Aminolevulínico/química , Ácido Aminolevulínico/metabolismo , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Ferroquelatase/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Heme Oxigenase (Desciclizante)/metabolismo , Humanos , Células MCF-7 , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Protoporfirinas/farmacologia , Tiossemicarbazonas/síntese química
18.
Metallomics ; 11(5): 994-1004, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31011727

RESUMO

Thiosemicarbazones (TSCs) are a class of strong metal ion ligands, which are currently being investigated for several applications, such as anticancer treatment. In addition to these ligands only, which exert their activity upon interaction with metal ions in cells, preformed metal-TSC complexes are also widely studied, predominantly with the essential metal ions iron, copper and zinc. Currently, it is unclear what the active species are, which complexes are present and what are their biological targets. Herein, we study the complexes of copper(ii), zinc(ii) and iron(ii) with three TSCs, PT, 3-AP (triapine) and Dp44mT, (latter two are currently in clinical trials), concerning their reactivity with glutathione (GSH) and Zn7-metallothionein (Zn7MT-1, 2 and 3). These two cysteine-containing molecules can have a major impact on metal-TSC complexes because they are abundant in the cytosol and nucleus, they are strong metal ligands and have the potential to reduce Cu(ii) and Fe(iii). Our results indicate that Fe(ii)-TSC is stable in the presence of typical cytosolic concentrations of GSH and Zn7MT. In contrast, all three Cu(ii)-TSCs react rapidly due to the reduction of Cu(ii) to Cu(i), which is then transferred to MT. This suggests that Cu(ii)-TSCs are rapidly dissociated in a cytosolic-type environment and the catalytic generation of reactive oxygen species by Cu(ii)-TSCs is stopped. Moreover, in the case Cu(ii)-Dp44mT, transmetallation with Zn(ii) from MT occurs. The reaction of Zn(ii)-TSCs is ligand dependent, from predominant dissociation for PT and 3-AP, to very little dissociation of Zn(ii)-Dp44mT2. These results indicate that GSH and Zn7MT may be important factors in the fate of Cu(ii)- and Zn(ii)-TSCs. In particular, for Cu, its chemistry is complex, and these reactions may also occur for other families of Cu-complexes used in cancer treatment or for other applications.


Assuntos
Cobre/metabolismo , Glutationa/metabolismo , Ferro/metabolismo , Metalotioneína/metabolismo , Tiossemicarbazonas/metabolismo , Zinco/metabolismo , Concentração de Íons de Hidrogênio , Ligantes , Espécies Reativas de Oxigênio/metabolismo , Espectrofotometria Ultravioleta , Tiossemicarbazonas/química
19.
Comput Biol Chem ; 80: 54-65, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30901601

RESUMO

Development of novel, safe and effective drug candidates combating the emerging drug resistance has remained a major focus in the mainstream of anti-tuberculosis research. Here, we inspired to design and synthesize series of new pyridin-4-yl-1,3,4-oxadiazol-2-yl-thio-ethylidene-hydrazinecarbothioamide derivatives as potential anti-tubercular agents. The anti-tubercular bioactive assay demonstrated that the synthesized compounds exhibit potent anti-tubercular activity (MIC = 3.9-7.81 µg/mL) in comparison with reference drugs Rifampicin and Isoniazid.We employed pharmacophore probing approach for the identification of CYP51 as a possible drug target for the synthesized compounds. To understand the preferable binding mode, the synthesized molecules were docked onto the active site of Sterol 14 α-demethylases (CYP51) target. From the binding free energy of the docking results it was revealed that the compounds were effective CYP51 inhibitors and acts as antitubercular agent.


Assuntos
Antituberculosos/farmacologia , Oxidiazóis/farmacologia , Piridinas/farmacologia , Tiossemicarbazonas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/metabolismo , Domínio Catalítico , Família 51 do Citocromo P450/química , Família 51 do Citocromo P450/metabolismo , Desenho de Fármacos , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/metabolismo , Sequestradores de Radicais Livres/farmacologia , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/metabolismo , Ligação Proteica , Piridinas/síntese química , Piridinas/química , Piridinas/metabolismo , Rifampina/farmacologia , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Tiossemicarbazonas/metabolismo
20.
Anal Bioanal Chem ; 411(11): 2383-2394, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30820631

RESUMO

Solid-phase microextraction (SPME) is an alternative method to dialysis and ultrafiltration for the determination of plasma protein binding (PPB) of drugs. It is particularly advantageous for complicated analytes where standard methods are not applicable. Di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) is a lead compound of novel thiosemicarbazone anti-cancer drugs, which entered clinical trials in 2016. However, this agent exhibited non-specific binding on filtration membranes and had intrinsic chelation activity, which precluded standard PPB methods. In this study, using a simple and fast procedure, we prepared novel SPME fibers for extraction of DpC based on a metal-free, silicon string support, covered with C18 sorbent. Reproducibility of the preparation process was demonstrated by the percent relative standard deviation (RSD) of ≤ 9.2% of the amount of DpC extracted from PBS by several independently prepared fibers. The SPME procedure was optimized by evaluating extraction and desorption time profiles. Suitability of the optimized protocol was verified by examining reproducibility, linearity, and recovery of DpC extracted from PBS or plasma. All samples extracted by SPME were analyzed using an optimized and validated UHPLC-MS/MS method. The developed procedure was applied to the in vitro determination of PPB of DpC at two clinically relevant concentrations (500 and 1000 ng/mL). These studies showed that DpC is highly bound to plasma proteins (PPB ≥ 88%) and this did not differ significantly between both concentrations tested. This investigation provides novel data in the applicability of SPME for the determination of PPB of chelators, as well as useful information for the clinical development of DpC. Graphical abstract.


Assuntos
Antineoplásicos/metabolismo , Proteínas Sanguíneas/metabolismo , Piridinas/metabolismo , Microextração em Fase Sólida/instrumentação , Tiossemicarbazonas/metabolismo , Adsorção , Animais , Bovinos , Cromatografia Líquida de Alta Pressão/métodos , Desenho de Equipamento , Ligação Proteica , Ratos , Silício/química , Microextração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos
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